Continuing Education Activity

The American Society of Hematology defines immune thrombocytopenic purpura (ITP) as isolated thrombocytopenia (platelet count less than 100,000/microL) with normal white blood cells and normal hemoglobin in the setting of a generalized purpuric rash. ITP was previously known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura. ITP without a secondary cause or underlying disorder is known as primary ITP and is the focus of this article. Secondary ITP is defined as ITP with an underlying cause or disorder, which includes drug-induced or systemic illness-induced (e.g., SLE, HIV, CVID, etc.). Severe ITP (generally when platelet counts are below 20,000/microL) warrants medical treatment. ITP is most commonly seen in children at any age, as well as in the adult population. This activity reviews the evaluation and management of immune thrombocytopenic purpura (ITP) and explains the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of immune thrombocytopenic purpura.
• Outline the typical presentation of a patient with immune thrombocytopenic purpura.
• Explain the common physical exam findings associated with immune thrombocytopenic purpura.
• Review the importance of improving care coordination amongst interdisciplinary team members to improve outcomes for patients affected by immune thrombocytopenic purpura.

Introduction

The American Society of Hematology defines immune thrombocytopenic purpura (ITP) as isolated thrombocytopenia (platelet count <100,000/microL) with normal white blood cells and normal hemoglobin in the setting of a generalized purpuric rash. ITP was previously known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura. ITP without a secondary cause or underlying disorder is known as primary ITP and is the focus of this article.[1] Secondary ITP is defined as ITP with an underlying cause or disorder, which includes drug-induced or systemic illness-induced (e.g., SLE, HIV, CVID, etc.).[1] Severe ITP (generally when platelet counts are below 20,000/microL) warrants medical treatment.

Primary ITP is further categorized into three phases based on the timing and continuation of symptoms.[1] Newly diagnosed ITP is defined as from the time of diagnosis to 3 months from diagnosis. Persistent ITP is the continuation of ITP from 3 to 12 months from initial diagnosis, and chronic ITP is the continuation of ITP after 12 months from initial diagnosis until resolution.

Etiology

The two most common inciting events include infection or immune alteration. Cases of ITP associated with infection usually have a preceding viral infection, the most common bacterial infection.[2] Antibodies develop against the viral or bacterial antigen, which cross-react with normal platelet antigens, a form of molecular mimicry.[2] The most common viral infections include HIV, hepatitis C, cytomegalovirus, and varicella zoster.[2]

Cases of ITP associated with immune alteration occur due to autoimmune conditions causing loss of peripheral tolerance and promoting the development of auto-antibodies. The most common autoimmune conditions include antiphospholipid syndrome, systemic lupus erythematosus, Evans syndrome, hematopoietic cell transplantation, chronic lymphocytic leukemia, common variable immunodeficiency, and autoimmune lymphoproliferative syndrome.[2]

There is a long list of medications known to cause ITP. The most common ones are mentioned here:[3][4]

• Abciximab
• Beta-lactam antibiotics
• Carbamazepine
• Eptifibatide
• Gold compounds
• Heparin
• Phenytoin
• Linezolid
• MMR vaccine
• Piperacillin
• Quinine
• Sulfonamides
• Vancomycin
• Tirofiban
• Rifampin
• Trimethoprim-sulfamethoxazole

Epidemiology

In children, the annual incidence is estimated to be between 1 and 6.4 cases per 100,000 people.[5] Researchers believe annual pediatric incidence is probably higher due to reported cases being based on symptomatic ITP needing hospitalization and not total ITP cases.[5] However, children can present at any age, but there is a peak incidence between the ages of 2 and 5 years, as well as another peak in adolescence. From infancy to childhood, there is a slight predominance of males over females. However, in adolescents to young adulthood (i.e., 18 to 45 years old), there is a predominance of the condition in females over males, consistent with higher levels of estrogen, which can promote autoimmunity in these patients.[6] In children, seasonal fluctuations have also been noted, with increased incidence in the spring and early summer consistent with viral infections.[5]

In adults, the annual incidence is estimated to be between 1 to 6 cases per 100,000 people.[5] However, ITP is more of a chronic disease in adults, so the prevalence is approximately 12 per 100,000 cases.[5] Peak incidence in adults occurs around 60 years old. However, incidence increases with increasing age.[7] Over the age of 60 years, there is a similar incidence in males and females.[5] Some studies have documented the increasing incidence of ITP with advancing age.[8]

Pathophysiology

The etiology of ITP is autoantibody (usually immunoglobulin G) mediated.[9] Patients with ITP develop autoantibodies against platelet membrane proteins, specifically glycoprotein (GP) IIb/IIIa complex, GP Ib/IIa, and GP VI.[9] The antibody-coated platelets are then cleared by tissue macrophages, specifically in the spleen, at an accelerated rate, leading to a shortened half-life of the platelet.[9] These same antibodies also inhibit platelet destruction, leading to thrombocytopenia.[9] However, an alternative mechanism has also been proposed involving T-cell-mediated cytotoxicity.[10] In this mechanism, cytotoxic T cells attack megakaryocytes in the bone marrow. However, the mechanism is not well understood.

History and Physical

History

Since ITP is mainly a diagnosis of exclusion, it is mainly seen in well-appearing patients with a history of mucocutaneous bleeding, the sudden appearance of a petechial rash, and/or bruising. The history should focus on any secondary causes of thrombocytopenia, bleeding, or bruising. About sixty percent of children diagnosed with ITP have a preceding viral illness within the past month.[11] Studies have also shown a small increased risk of ITP within six weeks after measles, mumps, and rubella (MMR) vaccination, as well as varicella, hepatitis A, and tetanus-diphtheria-acellular pertussis vaccinations in older children.[12]

Other secondary causes of thrombocytopenia should be explored in the history, including any systemic symptoms (i.e., fever, weight loss, anorexia, night sweats, or bone pain), exposure to any medications that can induce thrombocytopenia, any personal bleeding history, family history of bleeding or platelet disorders, recent infections, and any underlying conditions including rheumatologic diseases or liver disease. It is essential to ask about the medications used for shorter periods and beverages like "tonic water" and "jello shots" that contain quinine. Questions about bleeding symptoms, bruising, and petechiae should also be explored.

Physical Exam

Most children are well-appearing other than presenting with the classic petechial rash, which does not blanch when pressure is applied. In adults, about two-thirds may present with bleeding, ranging from a petechial rash, mucosal bleeding, or rarely hemorrhage.[13] The priority of the physical exam is on signs of bleeding, specifically of the skin and oral mucosa, as well as the presence of lymphadenopathy or hepatosplenomegaly, which suggests an underlying condition causing secondary ITP. Mucocutaneous bleeding presents as petechiae, purpura, or ecchymosis on the skin. It can also involve the nasal passages (epistaxis), buccal and gingival surfaces (gum bleeding), GI tract, genitourinary system, or vaginal bleeding. However, conjunctival or retinal hemorrhages are rarely seen in ITP.[14]

Evaluation

Initial Evaluation

Initial laboratory evaluation for children and adults should include a complete blood count with differential, a reticulocyte count, peripheral blood smear, blood type, and direct antiglobulin test (DAT), and if suspecting an underlying immunodeficiency, immunoglobulin levels.[15]

In ITP, the white blood count, hemoglobin concentration, red cell indices, and differential are usually normal, and the only abnormality seen is a platelet count of less than 100,000/microL.[15] If considerable blood loss has occurred, microcytic anemia can be seen on the CBC. If a patient had a recent infection, the white cell count could be high or low depending on the cause of the infection (i.e., bacterial cause showing high WBC vs. viral cause showing low WBC). The reticulocyte count is usually normal unless the patient presents with significant acute blood loss anemia.[15] On the peripheral blood smear, white and red blood cells typically have a normal appearance with a decreased number of platelets, and the platelets will be normal to increased size.[15]

If there are other findings seen on the peripheral smear, this may suggest another underlying cause of thrombocytopenia. For example, if WBC precursor cells (i.e., blasts) are seen on a peripheral smear, one must consider leukemia or lymphoma as the cause of thrombocytopenia.

If polychromasia, reticulocytes, or spherocytes are seen on peripheral smear, hemolytic anemia may cause thrombocytopenia, and if schistocytes are seen, microangiopathic hemolytic anemia may be the cause of the underlying thrombocytopenia. Therefore, blood type and direct antiglobulin test (DAT) are usually performed if the patient needs a blood transfusion, and DAT testing is generally negative.

Further Evaluation

For many adults and children, an initial bone marrow biopsy is no longer performed for a typical presentation of ITP. Bone marrow aspiration and biopsy are indicated if there are clinical, or laboratory signs suggesting malignancy or bone marrow failure (i.e., lymph node enlargement, splenomegaly, bone pain, fevers, unintentional weight loss, neutropenia, leukocytosis, atypical lymphocytes, or anemia) or the patient is unresponsive to treatment with glucocorticoids, IVIG, and/or anti-D immune globulin.[15]

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be performed in individuals with moderate or severe thrombocytopenia, those with planned invasive procedures, and those with concerns of overt bleeding.

Based on history and gastrointestinal symptoms, patients suspected with Helicobacter pylori infection should be tested for H. pylori.

Patients requiring splenectomy to treat ITP (or any other surgery) may often be screened for hypo- or hyperthyroidism before the procedure due to the increased risk of perioperative complications.

Vitamin B12 and folate levels should be measured in patients with dietary practices associated with decreased intake of B12, those with neurologic or psychiatric changes, and those with hypersegmented neutrophils on a complete blood profile.

Antiplatelet antibody testing is not recommended as it does not correlate with clinical outcomes.[16]

Treatment / Management

Initial Management

The management varies with bleeding severities as described below:

• Critical bleeding: Pericardial, intracranial, intraocular, intraspinal, retroperitoneal, or intramuscular bleeding with compartment syndrome or any other bleeding leading to hemodynamic instability. Immediate treatment with platelet transfusion, intravenous immune globulin (IVIG), and glucocorticoids is required. The platelet count is typically <20,000/microL and often <10,000/microL. However, it can also occur with a higher platelet count (e.g., between 20,000 and 50,000/microL) and require similar treatment. Other reasons for bleeding should also be investigated and treated, as thrombocytopenia is unlikely to be the only reason for the bleeding. It is often treated in the intensive care unit.
• Severe bleeding: Bleeding that does not meet the definition of critical bleeding but leads to a fall in hemoglobin of 2 g/dL. Requires urgent treatment with IVIG and glucocorticoids. Like critical bleeding, the platelet count is typically <20,000/microL and often <10,000/microL. It is also often treated in the intensive care unit.

• Minor bleeding: This is bleeding that does not meet any of the above criteria; minor skin bleeds, for instance. These patients require close observation. The general management of treating minor bleeding and severe thrombocytopenia with or without bleeding is similar. Most patients with minor bleeding (platelet count is often <50,000/microL) and those with platelet counts <20,000/microL are treated. Patients with platelet count ≥30,000/microL and not bleeding often do not require any treatment.[17] 

  The American Society of Hematology 2019 guidelines recommend that children with no bleeding or mild bleeding (i.e., bruising or petechiae) be observed with monitoring of bleeding regardless of platelet count. This includes repeat laboratory studies under the care of a pediatric hematologist to monitor platelet levels. Fifty to seventy percent of children will recover without intervention within three to six months from the initial presentation. For those children with non-life-threatening mucosal bleeding and/or decreased health-related quality of life, guidelines recommend prednisone 2 to 4 mg/kg/day (maximum 120 mg daily) for 5 to 7 days. For children where corticosteroids are contraindicated or not preferred, intravenous immunoglobulin (IVIG) or anti-D immunoglobulin can be used.[15]

The need for therapy requires the following assessment:

• Presence and type of bleeding
• Platelet count
• Other bleeding risk factors
• Any previous treatments

Critical Bleeding

• Platelet transfusion: 1 apheresis unit or 4 to 6 units of pooled platelet. It is the fastest way to increase the platelet count in critical bleeding. Repeated transfusions and other systemic therapies are needed as platelet count increases typically last less than one hour. Intravenous immunoglobulins (IVIG) may enhance the response to platelet transfusion.[18]
• IVIG and glucocorticoids: Their combined effect is perceived as augmentative.
  • IVIG is typically administered as 1 g/kg as a single dose and may be repeated the following day unless the platelet count is >50,000/microL.
  • Glucocorticoids are usually prescribed as one of the following regimes:
    • Methylprednisolone 1 g IV once daily for 3 days
    • Dexamethasone 40 mg IV once daily for 4 days
• Hemostatic therapies like tranexamic acid may also be given.

Severe Bleeding

• IVIG and glucocorticoids: Their combined effect is perceived as augmentative.
  • IVIG is typically administered as 1 g/kg as a single dose and may be repeated the next day unless the platelet count is >50,000/microL.
  • Glucocorticoids are usually prescribed as one of the following regimes:
    • Methylprednisolone 1 g IV once daily for 3 days
    • Dexamethasone 40 mg IV once daily for 4 days
• Hemostatic therapies like tranexamic acid may also be given.

Minor bleeding/low platelet count:

• Glucocorticoids are usually prescribed as one of the following regimes:
  • Prednisone 1 mg/kg/d for 7 to 14 days, followed by a gradual taper.
  • Dexamethasone 40 mg IV or orally once daily for 4 days

Anti-D, an immune globulin against the D antigen of the Rh blood group system, is sometimes used as an alternative in patients with RhD-positive blood group. However, it comes with US Food and Drug Administration (FDA) boxed warning for hemolytic transfusion reactions; hence, many clinicians are hesitant to use it.[19]

Second-line Therapies

The American Society of Hematology 2019 guidelines recommend that children with non-life-threatening mucosal bleeding and/or decreased health-related quality of life who do not respond to first-line therapies or who have chronic ITP should be trialed on a thrombopoietin receptor agonist (i.e., eltrombopag or romiplostim) first. If the child fails to respond to a thrombopoietin receptor agonist after a period of time, then rituximab should be used as the next therapy of choice. Splenectomy is usually reserved for those children with severe thrombocytopenia and severe hemorrhagic symptoms, which require multiple pharmacological interventions and should be delayed as long as possible due to the high potential for spontaneous remission and risk for asplenic sepsis. The current recommendation for splenectomy in children is waiting at least 12 months from initial diagnosis and waiting until the child is older than five years of age.[15]

The American Society of Hematology 2019 guidelines recommend adults with ITP who are dependent on corticosteroids or unresponsive to corticosteroids for three months or more or are considered chronic ITP; second-line therapies are recommended. These include thrombopoietin receptor agonists (i.e., eltrombopag or romiplostim, or avatrombopag), rituximab, and splenectomy. The choice of a second-line agent is more individualized based on the duration of ITP, the number of hospitalizations, comorbidities, and the desires of the patient. If a patient desires a long-term response and prefers to avoid surgery, then thrombopoietin receptor agonists are the therapy of choice. If a patient does not desire to take a medication for an extended period of time and also avoid surgery, then rituximab is the therapy of choice.

Administration of Second-line Therapies

• Rituximab:
  • The usual dose is 375 mg/m IV once a week for four consecutive weeks.
  • Use in hepatitis B virus (HBV) infected patients is avoided.
  • Progressive multifocal leukoencephalopathy (PML) has also been reported following rituximab for ITP.[20]
  • The initial response is 7 to 56 days.
  • Immunizations are given before administering rituximab as it may interfere with their response.

• Thrombopoietin receptor agonists (TPO-RAs):
  • Started at an initial low dose and titrated up as needed.[21]
    • Romiplostim
      • The dose ranges from 1 to 10 mcg/kg.
      • Typically started at  2 to 3 mcg/kg.[22]
      • The initial response is 7 to 14 days.
    • Eltrombopag
      • The initial dose is 50 mg daily.
      • 25 mg once daily in individuals of East-Asian ancestry or those with moderate or severe liver insufficiency[23]
      • The initial response is 7 to 14 days.
      • Reduced absorption with calcium-rich food
      • Supplements containing polyvalent cations such as iron, calcium, aluminum, magnesium, zinc, or selenium should be given at least four hours before or two hours after eltrombopag.
    • Avatrombopag
      • The initial dose is 20 mg once daily and is adjusted to keep platelets >50,000/microL.
      • The initial response is 3 to 5 days.
      • Less hepatotoxic
      • No interaction with dairy products

Splenectomy should be considered for those patients desiring a long-term response but should be delayed until after the first year of diagnosis due to the potential for remission within the first year.[15]

In 2018, the FDA approved fostamatinib, a spleen tyrosine kinase (Syk) inhibitor, as an option for patients whose disease is refractory to second-line treatments.[24][25] Other subsequent line treatment options include danazol or immunosuppressive agents like azathioprine, cyclosporine, and mycophenolate.

Platelets should be monitored one week after the change in dose/drug and every month once the therapy is stable. Moreover, platelets should be checked whenever there is a mucosal bleed or petechiae.

Differential Diagnosis

The differential diagnosis for thrombocytopenia includes but is not limited to the following:

• Leukemia, specifically acute lymphocytic leukemia (ALL), however, will have corresponding clinical and laboratory findings, including systemic symptoms (i.e., fever, joint pain, or weight loss), hepatosplenomegaly, lymphadenopathy, leukocytosis, and significant anemia (Hg <10).
• An active infection, including Epstein-Barr virus, cytomegalovirus, hepatitis C, and HIV-1.[26]
• Autoimmune hemolytic anemia (AIHA) will have corresponding clinical and laboratory findings, including anemia, jaundice, elevated reticulocyte count, spherocytes, and polychromasia.
• Systemic autoimmune disease, in which thrombocytopenia can be the presenting manifestation of an autoimmune disease, specifically for systemic lupus erythematosus (SLE) or autoimmune lymphoproliferative syndrome (ALPS).
• Some immunodeficiency syndromes, specifically common variable immunodeficiency (CVID), present with thrombocytopenia in the presence of recurrent infections.[27] Wiskott-Aldrich syndrome should be a consideration in a male with eczema, small platelet size, bleeding out of proportion to the platelet count, family history, and lack of response to ITP treatments. DiGeorge syndrome should be considered in those with hypocalcemia and cardiac anomalies with thrombocytopenia.
• Certain drug exposures, specifically heparin, quinidine, phenytoin, sulfonamides, valproate, and vancomycin, can cause thrombocytopenia.
• Bone marrow failure, as seen in aplastic anemia, can have associated thrombocytopenia. Hemolytic uremic syndrome (HUS) presents with hemolytic anemia, thrombocytopenia, acute kidney injury, and a recent history of gastrointestinal symptoms.
• Thrombotic thrombocytopenic purpura (TTP) presents with severe microangiopathic hemolytic anemia, thrombocytopenia, and neurologic symptoms (i.e., confusion, somnolence, or headache). Disseminated intravascular coagulation (DIC) presents with thrombocytopenia in the context of hemorrhage and thrombosis with end-organ damage due to sepsis, trauma, or malignancy.

Prognosis

Most children recover from ITP within three to six months from initial presentation, regardless of treatment.[11] Studies show approximately ten to twenty percent of children with ITP progress to chronic ITP, defined as thrombocytopenia for more than twelve months from initial diagnosis.[28] Risk factors associated with an increased risk of developing chronic ITP include older age at diagnosis, less severe thrombocytopenia at initial diagnosis, gradual onset of symptoms, absence of preceding infection or vaccination before ITP diagnosis, and absence of mucosal bleeding at presentation.[29] Spontaneous remission occurs in about 50% of cases after years from diagnosis in children with chronic ITP, many occurring within the first two years but can occur as long as five years from initial diagnosis.[30]

Children less than ten years of age with chronic ITP are more likely to undergo remission than older children.[31] Mortality from ITP in children is rare, mainly due to complications from catastrophic bleeding, specifically intracranial hemorrhage.[13] Most mortality and morbidity in pediatric chronic ITP result from complications of long-term immunosuppressive treatment, mainly infections.[32]

Most adults will reach a stable platelet count with one or more therapies. In about 10% of adults, spontaneous remission occurs most often within the first six months.[33] About one-third to two-thirds of those who do not undergo spontaneous remission will reach a stable platelet count with first-line treatments. The remaining adults affected with ITP will have refractory disease, requiring additional second-line therapies or eventual splenectomy. Cases have been reported where the initial ITP was induced through an autoimmune pathway. Subsequently, those adults went on to develop systemic lupus erythematosus or chronic lymphocytic leukemia; however, the overall risk is unknown.[34]

Mortality from ITP in adults is only slightly higher than in the age-matched population and is mainly due to complications from bleeding, similar to children.[13] Most patients with ITP are more likely to die of conditions unrelated to ITP than complications of ITP or treatment.[13]

Complications

Most complications associated with ITP in children and adults are correlated to the bleeding risk associated with low platelet counts, specifically when the platelet count is less than 20,000/microL. Most people affected with ITP will have bruising and petechiae.[15] Some patients with ITP may experience mucosal bleeding, such as epistaxis or gum bleeding.[15] In some severe cases, patients may have gastrointestinal tract bleeding causing heme-positive stools, hematuria, or menorrhagia.[15]

The most feared complication of ITP is intracranial hemorrhage (ICH). In newly diagnosed children, the risk of ICH is about 0.5% and is slightly increased in those children with chronic ITP, but still less than 1%. Most cases of ICH occur at platelet levels less than 10,000/microL.[13] Symptoms concerning ICH in both children and adults include headache, persistent vomiting, altered mental status, seizures, focal neurological findings, and/or recent head trauma.[13]

Urgent evaluation, including neuroimaging and treatment, is imperative should a patient have an ICH. Risk factors for ICH include very low platelet counts (< 10,000/microL), head trauma, use of antiplatelet medications, and severe bleeding.[13] Severe bleeding is defined as epistaxis lasting 5 to 15 minutes, GI bleeding, and/or any other severe mucosal bleeding requiring hospitalization or blood transfusion.[13]

Deterrence and Patient Education

Patient and family education on the diagnosis of ITP, bleeding risks associated with this disease, and proper treatment, especially compliance with medical therapy, is essential for patients.

Children with ITP should be restricted from activities associated with a bleeding risk from trauma when their platelet count is less than 30,000/microL. These activities include but are not limited to contact and collision sports (i.e., football, boxing, lacrosse, and hockey) or any other activities associated with a risk for head injury (i.e., baseball, soccer, skiing, or gymnastics). Both children and adults should avoid antiplatelet medications, which include aspirin, ibuprofen, and other nonsteroidal anti-inflammatories (NSAIDs). Anticoagulants (i.e., heparin, enoxaparin, warfarin) should also be avoided in patients with platelet counts less than 20,000/microL.[35]

Patients and caregivers must be counseled on proper treatment and when to seek medical care.

Pearls and Other Issues

An oral Bruton tyrosine kinase (BTK) inhibitor, rilzabrutinib, is under investigation for several immune-mediated disorders.[36]

Enhancing Healthcare Team Outcomes

Clinically significant ITP presents in both childhood and adulthood, making it a familiar diagnosis for all clinicians providing pediatric and adult care. While the pediatrician or primary care provider may be the first to discover the initial rash with an associated hematologic abnormality, coordination with an interprofessional team comprising hematologists, pathologists, pharmacists, and nurses familiar with ITP is necessary for optimal diagnosis and management. Care plans may include education on the diagnosis of ITP, bleeding risks associated with the disease, and proper treatment. Pharmacists should review the patient's prior medications (if any), coordinate with the prescribing clinician regarding the possible treatments for ITP, perform medication reconciliation, and communicate any concerns that may arise. Nurses will coordinate activities between specialists, serve as liaisons/contact points, and assist in patient counseling. Accurate and updated records are also a means of communication between various care team members. In addition, many patients and caregivers must undergo education to avoid certain sports and activities associated with an increased bleeding risk and medications, including aspirin and NSAIDS, to avoid further decreasing platelet counts. This interprofessional model will help drive optimal patient care. [Level 5]